Abstract) The skin provides primary defense against microbial invasion and infection. We have shown that the production of antimicrobial peptides (AMPs) by the skin is essential to this process and that abnormalities in AMPs can explain the pathogenesis of several human diseases. Recently, we have also shown that psychological stress leads to a decrease in the production of AMPs such as cathelicidins and beta-defensins. Our data led us to hypothesize that the suppression of AMP production by stress contributes to stress-related infections. Furthermore, we have found that catestatin, a stress-induced inhibitor of the acetylcholine receptor, acts to further regulate AMP production in the skin. The overall objectives of this research proposal are to understand the mechanism of stress-induced suppression of skin AMP production. Specifically, our aims are to: 1. Determine how glucocorticods alter antimicrobial peptide production in keratinocytes. Thus addressing the question: What AMPs are altered in keratinocytes exposed to glucocorticoids? 2. Understand if stress and glucocorticoids increase susceptibility to infection through action on cathelicidin. Thus addressing the question: Is cathelicidin, or other AMPs identified in aim 1, important mediators of stress-induced infections? 3. Determine if catestatin, a gene induced by stress, influences AMP production and function through the action of glucocorticoids. Thus addressing the question: Do glucocorticoids play an essential role in how catestatin modifys the AMP response of murine skin? Successful completion of these goals will address our long-term objective to improve Veteran's health by understanding events that lead to skin disease. The relevance of this study to Veteran's health is seen by the fact that infectious diseases and stress are a major heath care burden for this population. In the current proposal we will continue a previously highly successful study of antimicrobial peptides, now turning to analysis of the mechanism by which stress changes antimicrobial function of the skin. Our study will approach this problem from a novel direction and provide the potential for discovery of previously unknown antimicrobial molecules and immune regulatory systems. Therefore, we hope to advance understanding of elements involved in infectious disease and stress, and provide increased opportunity to better diagnose and treat these disorders in the veteran population. PUBLIC HEALTH RELEVANCE: Project Narrative Relevance to Veterans Health. Infectious and inflammatory diseases of the skin are a major heath care burden for the veteran. Through the study of antimicrobial peptides we have made important advances in understanding how some of these diseases are controlled. We have discovered much about the etiology of rosacea and why patients with atopic dermatitis are susceptible to infection. The later impacts the capacity to administer live viral vaccines such as the smallpox vaccine. In the current proposal we will continue to study antimicrobial peptides, now turning to analysis of the mechanism by which stress changes antimicrobial function of the skin. Like infectious and inflammatory diseases, stress is a significant health concern of the veteran. Our study will approach this problem from a novel direction and provide the potential for discovery of previously unknown antimicrobial molecules and regulatory systems. Therefore, we hope to advance understanding of elements involved in infectious disease and stress, thereby providing increased opportunity to better diagnose and treat these disorders in the veteran population.